L20 Hormonal drug delivery Flashcards
1
Q
Why do we have dosage forms
A
- Drug often in powder form
- Tiny doses of drug (mg or mcg quantities)
- Bulk up with excipients (such as water, lactose)
2
Q
Why do we have different dosage forms?
A
- Different clinical conditions
- Different types of patient
- Different routes of administration
- Different physicochemical properties of drug
3
Q
Factors to consider when designing dosage forms
A
- Drug factors (solubility, partition coefficient, pKa, stability, MWt)
- Biopharmaceutical factors (absorption, bioavailability, route of administration)
- Therapeutic factors - disease, patient, route, local vs systemic delivery
4
Q
Types of hormones
A
- Modified amino acid derivatives
- Peptide and proteins
- Steroids
- Eicosanoids
5
Q
What are modified amino acid derivatives derived from
A
- Derived from tyrosine and tryptophan
6
Q
Examples of modified amino acid derivatives
A
- Dopamine, thyroxine
7
Q
What are peptides and proteins derived from
A
- Derived from amino acids
8
Q
Examples of peptides and proteins
A
- Neuropeptides (vasopressin), pituitary hormones(gonadotropins), GI hormones (insulin)
9
Q
What are steroids derived from
A
- Cholesterol
10
Q
Examples of steroids
A
- Sex hormones (testosterone)
- Corticosteroids (hydrocortisone)
11
Q
What are eicosanoids derived from
A
- Derived from lipids
12
Q
Examples of eicosanoids
A
- Prostaglandins, leukotrienes
13
Q
Main feature of modified amino acid derivatives
A
- Generally orally active
14
Q
Main features of peptide and proteins
A
- Vary considerably in size from 3 amino acids to large, multisubunits glycoproteins
- Susceptible to enzymatic degradation in GIT
- Low absorption
15
Q
Main features of steroids
A
eg. sex hormones
- Variable absorption
- Susceptible to extensive first pass hepatic metabolism
- Orally active BUT systemic Side effects
16
Q
Give examples of when you might not want systemic delivery of a drug
A
Might not want systemic delivery of a drug if:
- Side effects eg. corticosteroids
- Bioavailability is low eg. peptide hormones, sex hormones
17
Q
Examples of excipients
A
- Diluents/fillers eg. lactose, water
- Surfactants eg. polysorbates
- Lubricants eg. Mg sterate
- Disintegrants eg. starch
- Viscosity enhancing agents eg cellulose derivatives
- Flavours, colours, perfumes
- Sweetening agents
- Preservatives
18
Q
Features of local delivery
A
- Site of administration = site of action
- Rapid onset of action
- Less drug required
- Absorption into the blood stream is not required
- Absorption into the blood stream can lead to unwanted side effects
19
Q
Why might corticosteroids be administered locally via different dosage forms
A
To avoid systemic side effects, need many different dosage forms
Intra-articular injections cortisone - tennis elbow
Creams and ointments betamethasone - eczema
Inhalers e.g. beclomethasone for asthma
Eye drops dexamethasone for inflammatory conditions of eye
Suppositories hydrocortisone inflammatory conditions of rectum
20
Q
Factors to consider when administering modified amino acid derivatives and corticosteroids
A
Drug factors - low dose required
Biopharmaceutical factors - which route? orally bioavailable
Therapeutic factors - local vs systemic delivery
21
Q
Factors to consider when administering peptide hormones eg insulin
A
Drug factors - peptide hormone, large molecule MW - 5800 Da
Biopharmaceutical factors - not absorbed after oral administration
Therapeutic factors - need systemic action, aim to mimic insulin secretion by normal pancreas - basal and bolus
22
Q
Why are peptide hormones not absorbed after oral administration
A
- Not absorbed after oral administration because of enzymatic degradation in lumen of GIT
- Any that survives can’t readily cross GI epithelium into blood because too large
23
Q
How are insulins characterised
A
Insulins characterised by differences in:
Onset - how quickly they act
Peak - how quickly they achieve max impact
Duration - how long they last
Route of delivery - subcutaneous, inhaled
24
Q
When are rapid-acting insulins used
A
- Rapid-acting insulins are used in insulin pumps, also known as continuous subcutaneous insulin infusion (CSII) devices
- When delivered through a CSII pump, the rapid-acting insulins provide the basal insulin replacement, as well as the mealtime and high blood sugar correction insulin replacement
25
Advantages of pulmonary route - systemic delivery
- Large surface area (80-140 m2)
- Thin epithelial barrier (0.1-0.2 um)
- Good blood supply (100% cardiac output)
- Avoids harsh environment of GI tract
- Avoids first-pass hepatic metabolism
26
When is rapid-acting inhaled insulin taken
- Taken at the beginning of each meal
27
What is inhaled insulin taken in combination
- Used in combination with a long-acting injected insulin
28
Factors to consider when administering sex hormones
Drug factors - steroid, lipophilic, MW - 270 Da
Biopharmaceutical factors - variable absorption after oral administration, extensive first pass hepatic metabolism, short t1/2
Therapeutic factors - systemic delivery required but try to avoid oral route. Either cyclical or continuous administration required
29
Why do we need alternatives to oral route of administration
- To increase bioavailability
| - To offer sustained release
30
Alternative routes of administration to the oral route
- Parenteral route - IM injection, implant
- Transdermal route - patch or gel
- Intranasal route - spray
- Buccal route - mucoadhesive system
- Vagina - gel
31
Features of IM injections
Oily injections - sustained release
- Testosterone enantate (caster oil)
- Testosterone decanoate, isocaprate, phenylproprionate and proprionate, undecanoate
Implants - sustained release
- Nexplanon (progestogen-nly contraception)
32
Features of oily injections - IM injection
- Sustained action because of lower rate of partition from oily vehicle into aqueous environment of tissue
- Ester form of testosterone - DEPOT preparation - every 2-3 weeks
- Requires esterases at injection site to cleave active drug from 'pro' drug
33
Effects of ester at position 17
- Decreases water solubility
- Increases oil solubility
- Deactivates molecule - can't bind to androgen receptor
- Ester cleaved/hydrolysed in blood - restores-OH so can attach to receptor
34
How does release of steroid molecules from oily depots of long-chain esters in muscle tissue occur
- Oil has some affinity for water and thus allows penetration of water; the ester is hydrolysed at the surface of the droplet
35
Effect of total surface area of the droplet on the pharmokinetics of the drug
- The total surface area of the droplet can influence release rate and hence pharmokinetics of the drug
Droplet dimenions and total surface area influenced by:
force of injection
viscosity and surface tension of oil phase
size of needle
environment into which it’s injected – exercise can increase plasma levels by increasing surface area of droplet.
36
What is an etonogestrel(nexplanon) implant
The etonogestrel implant is a single-rod progestin contraceptive placed subdermally in the inner upper arm for long-acting reversible contraception in women
37
How is etonogestrel implant delivered
- Sub dermal implantation
- Provides effective contraception for up to 3 years unless BMI greater than 35 kg/m2 in which case, may not provide effective contraception in 3rd year
38
Advantages of intranasal administration - systemic
- Large surface area (-180cm2)
- Highly vascularised
- Avoids first pass hepatic metabolism
- Good bioavailability for low MW compounds
Product on the market - desmopressin
39
Disadvantages of intranasal administration - systemic
- Mucociliary clearance
- Metabolic activity
- Poor bioavailability for high MW compounds
40
Features of buccal administration - systemic
Mucoadhesive testosterone buccal delivery system:
- Applied twice daily
- Adheres to gum or inner cheek
- Sustained release of testosterone through buccal mucosa
- Eating, tooth brushing, mouthwashing, chewing gum and alcoholic beverages have no significant effect on use and absorption from device
41
How does the mucoadhesive testosterone buccal delivery system work
- When applied the device begins to hydrate and testosterone is absorbed through the gum and inner cheek surfaces that are in contact with it.
- Venous drainage from mouth is to superior vena cava, therefore avoids first-pass hepatic metabolism.
42
Physiologic levels of testosterone
300 - 1050 ng/dL
43
Changes in serum testosterone levels after buccal administration - systemic
- Following initial application, serum testosterone rises to a max within 10-12 hours
- Steady state levels are usually obtained after first two systems are applied
- When removed and not reapplied, serum testosterone levels fall to below normal range in 2-4 hours
44
Features of vaginal administration - systemic
- Self-insertion and removal
- Continuous release
- Good patient compliance
Bioadhesive vaginal gel (crinone) progesterone released over 25-50 h
45
What is crinone
- Micronised progesterone and polymer polycarbophil in an oil in water emulsion system
- Polymer, which is insoluble in water, swells within the vagina and forms a bioadhesive gel coating on the walls of the vagina. This allows progesterone to be absorbed through the vaginal tissue over 25 – 50 hours.
Product used to assist reproduction.
46
Vaginal administration (local) - device
- Vaginal ring (estring)
| - Estradiol released over 90 days
47
What is an estring used for
- Treatment of urogenital symptoms associated with postmenopausal atrophy of the vagina
48
Example of vaginal administration (local) - pessary
- Estradiol 10 mcg vaginal tablets (inserts) (vagifem)
49
What is mirena
- intrauterine device (IUD) with progestogen, sold under the brand name Mirena among others, is a intrauterine device that releases the hormone levonorgestrel
50
What type of contraception does progestasert (mirena) provide
- Progestasert (mirena) provides local rather than systemic contraception
- May inhibit sperm survival and/or alter uterine environment to prevent nidation
51
Advantages of mirena
- Uses natural hormone at much lower dose than by other routes
- Don't need to take/admin daily
- No estrogens
- T-shaped device for comfort, safety and retention - minimal mechanically - induce irritation
- Hormonal action confined to uterus
52
Eicosanoid hormones
- Prostaglandin E2 (prostin E2, dinoprostone)
- Vaginal gel
- Vaginal pessary/tablet (propess)
53
Duration of PGE2 release
- PGE2 released over 12 hours, local action to ripen cervix
54
What is PGE2 indicated for
- Indicated for the initiation and/or continuation of cervical ripening at or near term when need to induce birth.
